Author address:

Pfizer Inc., Groton, CT, Projections Res. Inc., Phoenixville, PA.

Abstract:

Background The objective was to describe PK of VOR and ANID in a subset of IA patients (n = 305) from a Phase 3 study of efficacy, safety and tolerability of VOR plus ANID versus VOR alone [VOR 6/4 mg/kg intravenous (IV) q12h 8594; 300 mg oral q12h; ANID 200/100 mg IV q24h]. Methods Previously developed population PK models were adopted to describe the sparse PK data (ANID: 453 points, VOR: 965 points) from IA patients using a nonlinear mixed effects approach. VOR was a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; ANID was a two-compartment model with first-order elimination. Attempts were made to explore new potential covariates. Results Previous models were successfully fit to the current data with few modifications. For both drugs, to accommodate the pre-study drug levels (prior treatment was allowed per protocol), a rate parameter was used to mimic an infusion. For VOR, the Normal-Inverse-Wishart prior approach was implemented to stabilize the model. No new covariates were identified for VOR and ANID. PK parameter estimates of VOR and ANID are in agreement with those reported previously except for VOR clearance (the nonlinear component which is nominal). VOR total clearances in IA patients and healthy subjects were not appreciably different. Estimated exposures of VOR and ANID in IA patients are tabulated. At
4 mg/kg IV, VOR exposure tended to increase slightly as
age, weight or body mass index increased. The magnitude
of the changes in exposure associated with age and body
size was not considered clinically significant as they were
similar in magnitude to the variability in exposures at a
given age or body size. Conclusion Estimated VOR
exposures in IA patients at 4 mg/kg IV were slightly higher
than those reported in healthy adults (eg, average AUC0-
12:~46% higher), noting that ~30% of them were on
(es)omeprazole and ~20% of them were >65 years old.
Estimated ANID exposures in IA patients were comparable
to those reported in the general patient population.